O-128 Letrozole co-treatment during ovarian stimulation in antagonist cycles augments follicle growth and exerts pronounced effects on endocrinology: a randomized controlled trial

Abstract

Study question What are the endocrine and paracrine effects of letrozole (LZ) co-treatment during ovarian stimulation (OS) and is follicle growth and recruitment affected? Summary answer Letrozole induces marked changes in the follicular and luteal phase endocrinology causing potentiation of follicle growth and corpus luteum function without affecting follicle recruitment. What is known already Letrozole is a 3rd generation aromatase inhibitor that is well-established as an effective ovulatory agent, while its possible benefits in standard in vitro fertilization (IVF) protocols are less thoroughly investigated. Study design, size, duration Double-blinded, placebo-controlled, randomized study with LZ or placebo intervention during OS for IVF treatment, a preceding baseline natural cycle, and a succeeding follow-up visit, in total three consecutive cycles. Participants were enrolled between August 2016 and November 2018. Participants/materials, setting, methods Thirty-one healthy, normo-responding women underwent a natural baseline cycle and an antagonist stimulation cycle with either LZ 5 mg/day (n = 16) or placebo (n = 15) during the follicular phase. Every third day, monitoring of follicle count and -growth and blood analyses of 12 endocrine and paracrine parameters were performed. Follicle recruitment was correlated to endocrine parameters, and differences in follicle recruitment, follicle growth and hormone parameters between groups were assessed. Main results and the role of chance In the LZ group, the number of follicles > 16 mm at oocyte pick up was increased (+2.0, 95% CI [0.1;3.8], p = 0.036), while the total number of follicles were the same (+0.2, 95% CI [-5.8;6.1], p = 0.958). The FSH concentration was increased in the LZ group at stimulation day 5 (p < 0.05), though the total FSH consumption during OS was similar (difference: -20 IU, 95% CI [-175;136], p= 0.794). Letrozole co-treatment suppressed oestradiol (E2) concentrations in the follicular phase (area under the curve (AUC) -62%, p < 0.001) and luteal phase (AUC -31%, p = 0.046). We found increased follicular phase LH (AUC +20.5%, p = 0.033), androstenedione (AUC +22%, p = 0.016), testosterone (AUC +33%, p = 0.013), and 17-OH-progesterone (+132%, p = 0.027). Interestingly, the corpus luteum (CL) output in the LZ group was increased with elevated luteal phase progesterone (AUC +35%, p = 0.043), Inhibin A (AUC +67%, p = 0.011), androstenedione (AUC +22%, p = 0.006), and testosterone (AUC +22%, p = 0.012). Hormone parameters were similar between groups at the follow-up visit. There was no effect of LZ co-treatment on recruitment of the next follicle cohort (p = 0.821). Limitations, reasons for caution This study included a relatively small, selected group of healthy women with an expected normal ovarian function and reserve, and the effects of LZ may therefore be different in other patient groups. Wider implications of the findings We confirm previous findings concerning increased follicle growth, increased endogenous FSH and androgen production, and support the rationale for use of LZ co-treatment as a form of endogenous androgen priming sensitizing the follicle to FSH. Letrozole appears to improve the luteal phase with better stimulation of CL and P4 secretion. Trial registration number NCT02939898